An immune response occurs only if a T lymphocyte has been able to recognize the foreign antigen in association with a self molecule encoded by the major histocompatibility complex (MHC). These molecules expressed on antigen-presenting cells are the polymorphic class II MHC antigens. Most foreign antigens must be processed in order to bind to MHC molecules. Antigen processing for presentation by class II molecules generally involves endocytosis of antigen into an acidic compartment through which newly synthesized class II molecules are passing on their way to the cell surface. Once at the cell surface, the foreign peptide/MHC class II complex interacts with the T cell receptor and the CD4 molecule expressed on the antigen-specific T cell. The aim of this project is to define the function of human class II molecules in their interaction with T cells and the requirements for class II-restricted processing and presentation of viral antigens to CD4-positive T cells. It has been demonstrated that a cytosolic antigen was endogenously processed in infected cells for class II-mediated presentation. Most interestingly, the processing pathway involved was different from the one utilized for presentation by class I molecules. This unsuspected presentation of endogenous proteins by class II molecules has important implications on the T cell repertoire selection, on T cell tolerance, and on autoimmunity. Several staphylococcal toxins bind to class II molecules and have a strong mitogenic effect on T cells, stimulating families of T cells with particular VBeta chains of the TCR. These toxins are representative of the newly described superantigens, antigens that do not require processing for presentation. Using a direct binding assay with normal and mutated molecules expressed on transfected cells, it was shown that the toxic shock syndrome toxin (TSST-1) required sequences in both Alpha-helices of the Alpha1 and Beta1 domains of the mouse class II IA molecule for binding. In addition, a critical residue (histidine 81) was identified in the Alpha-helix of the Beta1 domain of HLA-DR1 molecules that controls binding of superantigens SEA and SEE.